L21 Targeted Cancer therapy Flashcards
Define cancer at different biological levels: molecular, cellular, tissue
- Molecular level: Abnormalities in DNA due to exogenous carcinogens, DNA replication, inherited causes activation of oncogenes or inactivated tumour suppressor genes.
- Cellular level: Cancer is the disease of populations of cells that live, grow and spread and invade without respect to normal limits- gaining the hallmark phenotypic characteristics for survival
- Tissue level: Cancer is characterised by growth and invasion of 1 tumour, metastasis and distant effects of widespread disease, and systemic effects of paraneoplastic syndromes- hormonal/immune.
What is cytotoxic chemotherapy vs targeted chemotherapy
Cytotoxic chemotherapy: targets cells in the mitotic cell cycle without discriminating between normal and diseased cells. Works off the principle that there are higher numbers of cycling cells in tumours. Adverse effects due to inhibiting cycling in normal cells.
Targeted therapy: Drug treatment that interferes with specific molecules needed for tumour development and progression.
What are the two types of targeted cancer therapies
Small Molecular Weight Drug: (nib) block specific enzymes or growth factor receptors
recombinant humanised Monoclonal antibodies (mab) bind to Growth factors or their receptors
What is the clinical indications, mechanism of action and molecular target of Imatinib and adverse effects
CI:
Chronic myeloid leukaemia due to chromosomal translocation/unique fusion protein -> bcrabl
GIST: GI stromal tumours cause by point mutation activating c-Kit
Both lead to unrestricted tyrosine kinase activity.
MolTarget: Imatinib binds to ATP binding site on BCRabl and c-Kit tyrosine kinase to inhibit tyrosine kinase activity.
Adverse effect: generally well tolerated.
What is the clinical indications, mechanism of action and molecular target of Gefitinib and adverse effects
CI:
Non-Small cell lung cancer due to point somatic mutation/deletions and gene amplification of the EGFReceptor which leads to permanent tyrosine kinase activity independent of ligand binding.
MolTarget: SMW selective inhibitor of EGFR- binding the ATP binding site.
Adverse effects: acne like skin rash, GI nausea and diarrhoea.
What is the clinical indications, mechanism of action and molecular target of Trastuzumab and adverse effects
CI: Breast cancer with multiple copies of the Human Epidermal Growth factor receptor 2 gene lead to multiple HER-2 receptors on the cell surface, (tested by FSH).
MolTarget: Monoclonal antibody selectively targets the extracellular domain of the HER2 receptor protein
Adverse effect profile: infusion related reactions/hypersensitivity
What is the clinical indications, mechanism of action and molecular target of Sunitinib and adverse effects
CI: Renal cell cancer caused by mutation/silencing in loss of the von Hippel Lindau tumour suppressor gene. Loss of the protein turns on a molecular pathway that imitates hypoxia signals- leading to RTK activation. Associated with this is increased production of VEGF which induce angiogenesis to try and increase blood supply.
Mol Target: Small MW inhibitor binding to ATP site to inhibit tyrosine kinase activity on VEGF and platelet derived growth factor receptors.
Adverse effect: hypertension, haemorrhage and cardiac failure
What are the main targets of targeted cancer therapies
- Inhibiting the protein products of oncogenes that have initiated the cancer and driving its progression - eg. Growth factor signal pathway- tyrosine kinase
- Inhibiting Tumour induce blood vessel growth by secreting angiogenic factors: VEGF, BFGF
Otherwise tumour suppressor genes are harder to target because they have been deleted or mutated. These would have coded for proteins promoting apoptosis or repressing cell cycle.
